The present invention relates generally to the treatment of patients using chemotherapy agents. More specifically, the present invention relates to reducing or preventing side effects caused by chemotherapeutic agents.
Cancer can develop in any tissue of any organ at any age. Many cancers detected at an early stage are potentially curable. The principal objectives of cancer screening and early diagnosis are: (1) to decrease cancer mortality; (2) to lead to less radical therapy; and (3) to reduce financial costs. Merck Manual, 16th Edition, 1263, 1269 (1992).
Successful therapy must be focused on the primary tumor and its metastases, whether clinically apparent or microscopic. Thus, local and regional therapy, surgery, or radiation must be integrated with systemic therapy (e.g. drugs). Id. at 1275.
The ideal antineoplastic drug will destroy cancer cells without adverse effects or toxicities on normal cells. Unfortunately, no such drug exists. Id. at 1277. As a result, patients receiving antineoplastic drugs often must endure the toxic side effects of such drugs.
Among other chemotherapeutic/immunosuppressive drugs, cyclophosphamide is an essential component of many effective antineoplastic therapies. Cyclophosphamide has a very broad clinical spectrum of activity. Calabresi, P. and B. A. Chabner, Antineoplastic Agents: Cyclophosphamide, In, Goodman and Gilman's The Pharmacological Basis of Therapeutics, Eighth Edition, pp. 1216-1218 (1990). Because of its potent immunosuppressive properties, cyclophosphamide is used in controlling transplanted organ rejection and nonneoplastic immune disorders. In fact, cyclophosphamide, an oxazaphosphorine alkylating agent, is used in over 200,000 patients a year to treat neoplastic, immune mediated, and transplant related diseases.
Unfortunately, as with other chemotherapeutic/immunosuppressive drugs, cyclophosphamide has a significant dose dependent toxicity. See Physicians' Desk Reference, 44th Edition, p. 745 (1990). In addition, using cyclophosphamide results in a high potential for inducing sterility, teratogenic effects, mutations and cancer.
The occurrence of sterile, hemorrhagic cystitis is the most common therapy-limiting side effect of cyclophosphamide. Hemorrhagic cystitis occurs in up to 78% of the patients treated with cyclophosphamide. Grinbert-Funes, D. J., C. Sheldon, and M. Weiss, The Use of Prostaglandin F.sub.2 Alpha for the Prophylaxis of Cyclophosphamide Induced Cystitis in Rats, 144(6) J Urology, pp. 1500-1504 (1990). Although the basis for the injury to the urinary system is not completely understood, cyclophosphamide metabolites excreted in the urine are thought to induce cystitis. Physicians' Desk Reference, p. 745. Specifically, an active metabolic product of cyclophosphamide, namely acrolein, is thought to cause hemorrhagic cystitis.
Several sulphur containing materials have shown some success in preventing or reducing hemorrhagic cystitis. Namely, researchers have reported the use of N-acetylcysteine, 2-mecapthoethane sulfonate (Mesna), disodium 2-2'-dithio-bis-ethane sulfonate (Dimesna), and reduced glutathione as having some effect in reducing this side effect. Grinbert-Funes, D. J., et al, supra, at 2; Habs M. R., et al, Prevention of Urinary Bladder Tumors in Cyclotphosphamide-Treated Rats by Additional Medication With the Uroprotectors Sodium 2-mercaptoethane Sulfonate (Mesna) and Disodium 2,2'-dithio-bis-ethane Sulfonate (Dimesna), Cancer 51:606-609 (1983); and Nobile, M. T., et al, A Preliminary Clinical Study of Cyclophosphamide With Reduced Glutathione as Uroprotector, Tumori 73(3): 257-258 (1989).
One of these compounds, Mesna, is a synthetic sulfhydryl compound and is currently marketed as Mesnex.RTM. Injection. This Mesnex.RTM. Injection product is marketed as a detoxifying agent to inhibit hemorrhagic cystitis. Mesna forms a nontoxic thioether with acrolein, and has an added inhibitory effect on the spontaneous release of acrolein from hydroxylated cyclophosphamide in urine. Rats given Mesna in conjunction with cyclophosphamide experienced a significant decrease in ulceration, inflammation and edema of the bladder compared to those treated with cyclophosphamide alone.
These known compounds suffer certain drawbacks. Further, these compounds do not address other side effects of chemotherapeutic treatment such as induction of cancer, alopecia and sterility.